Declining testosterone levels – which is commonly seen in men as they get older - are associated with reduced lean body mass, muscle strength, and self-reported and performance-based measures of physical function.1-3 Evidence for a causal relationship between testosterone levels and lean body (muscle) mass comes from intervention studies which have shown that testosterone treatment consistently increases whole-body and appendicular lean body mass (which is a proxy for muscle mass).1,4-7

Here we summarize the results of a secondary analysis of muscle performance, physical function, and lean body mass in the TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) Trial, which is one of the longest duration randomized controlled trial (RCT) of testosterone treatment available to date.8

Men in the placebo group showed a decline in lean body mass, muscle strength and power, suggesting that long-term testosterone treatment not only prevents the age-related loss in muscle function, but actually improves muscle function.

Treatment effects tended to wane over time in parallel with the dropping testosterone levels. This underscores the importance of long-term adherence to testosterone treatment in order to realize benefits.

What is known

Well-documented increases in muscle mass with testosterone treatment 1,4-7 has stimulated interest in investigating the anabolic applications of testosterone to improve physical function and reduce the burden of disability in older adults.9-16 However, the effects of testosterone treatment on muscle performance and physical function have been inconsistent in previous studies, which were limited by relatively short duration, small sample sizes, and differences in testosterone doses, regimens, and achieved testosterone levels.1,4-7,17,18

In addition, the effects of testosterone on other important measures of muscle performance, such as muscle power and fatigability, have not been well researched. Muscle power - the rate at which a muscle generates force - is more strongly associated with measures of physical function than muscle strength, and declines faster than strength with aging.19,20 Muscle fatigability (endurance) is related to the ability to delay onset of muscle fatigue, especially when performing movements at high workloads.21,22 The importance of fatigue resistance in older people has gained increasing recognition.23 Older adults have greater fatigue-related reductions in peak velocity compared with young adults for both the elbow flexor (biceps) and knee extensor (quadriceps) muscles. Importantly, less fatigability (i.e. greater endurance) of the knee extensor muscles has been shown to be associated with longer walking endurance and balance in older adults.24 Diabetic patients are especially prone to premature muscle fatigue.25 Besides the reduction in strength, muscle dysfunction in type 2 diabetes is characterized by higher fatigability (reduced endurance) that affects both upper and lower body muscles.25 This effect is independent of the presence of diabetic complications and may be a more sensitive marker of muscular dysfunction than muscle strength.25

What this study adds

The TEAAM trial enrolled subjects who were community-dwelling men aged 60 years or older with low to low-normal testosterone levels, defined as total testosterone levels between 3.5–13.9 nmol/L (100 and 400 ng/dL) or free testosterone level less than 174 pmol/L (50 pg/mL) obtained in a fasting morning sample. None of the subjects were engaged in resistance exercise training before or during the 36 months of the study. These men are similar to a substantial fraction of middle-aged and older men receiving testosterone prescriptions.26,27

Intervention and Measurements

Subjects were randomly assigned to receive either 7.5 g of 1% testosterone gel (75 mg of testosterone) or placebo gel daily for 3 years. If the total testosterone level was lower than 500 ng/dL (17.3 nmol/L), the testosterone dose was increased to 10 g daily; if it was higher than 900 ng/dL (31.2 nmol/L) the dose was reduced to 5 g. Testosterone levels were measured at 6, 18, and 36 months. Lean body mass was measured by DEXA (dual energy x-ray absorptiometry).

The stair-climbing test was used as a measure of physical function, because of its higher ceiling and stronger association with leg strength than some other measures of physical function, such as gait speed.17 Performance in a loaded stair climb test, in which participants carried a load while ascending stairs, was also assessed.

Maximal strength was assessed using the 1-repetition maximum (1-RM) method for seated leg-press and chest-press. Power was measured using the same machines, which also provided measurement of force and velocity (and hence, power). Muscle fatigability was assessed by having subjects perform as many full range-of-motion repetitions as possible at a fixed cadence of 4 seconds per repetition with a load equal to 80% or 70% of the baseline 1-RM for the leg press and chest press, respectively. The same absolute loads were used for all tests over the 3-year study.

After 3 years, testosterone treated men had gained 0.7 kg lean body mass while placebo treated men had lost lean body mass, amounting to a significant between-group difference of 0.9 kg. Testosterone treated men showed increased performance in stair-climbing power (both unloaded and loaded), as well as chest and leg strength and power, while placebo treated men had reductions in these performance parameters.

It was concluded that compared to placebo, testosterone treatment in older men for 3 years resulted in significantly greater improvements in stair-climbing power, muscle mass, and power.8 Clinical meaningfulness of these treatment effects and their impact on disability in older adults with functional limitations remains to be studied.

Commentary

This study is notable in that it shows that long-term testosterone treatment for 3 years increases lean body mass, muscle strength and power in 60 year old men who are representative of a large majority of middle-aged and older men receiving testosterone prescriptions.

Interestingly, these men just had low-normal testosterone levels and were not diagnosed with testosterone deficiency (which requires presence of both low testosterone levels and symptoms indicative of testosterone deficiency). And they were not engaging in resistance exercise training during the 3 year-long study. Despite absence of exercise and not being diagnosed with testosterone deficiency (or hypogonadism), testosterone treatment did increase lean body mass, muscle strength and power. It should also be highlighted that the treatment effects tended to wane over time in parallel with the dropping testosterone levels. This underscores the importance of long-term adherence to testosterone treatment in order to realize benefits.

An advantage of this study is that it evaluated strength in large muscle groups (legs and chest) as opposed to handgrip strength. The main limitation of the hand grip test is that hand grip uses a small muscle group and is not well correlated with measures of overall muscular strength as determined by measurements of strength using large muscle groups.6,28 Assessing strength of larger muscle groups likely provides a better overall index of muscular strength, and a more accurate intervention effect of testosterone treatment.

Unique to this 3-year study of testosterone administration in older men is the assessment of muscle power and endurance. Because muscle power - which is lost with aging at a faster rate than strength - is more strongly associated with functional performance in activities such as stair climbing, walking, and rising from a chair 19, it is important to assess the effectiveness of anabolic therapies on muscle power. Testosterone treated men significantly increased both lower and upper extremity power more than men receiving placebo. The changes in leg-press and chest-press power were significantly associated with changes in stair-climbing power, which reinforces the role of muscle power in performance of functional activities.

Muscle fatigability, assessed by the number of repetitions to failure at 80% of baseline chest press and leg-press strength (1-RM) was not affected in this study. Because endurance is on a continuum with muscle strength 29, the small strength gains over the course of the study in the testosterone treated men may not have been adequate to impact endurance. Greater gains in strength and hence endurance would likely have been seen if resistance exercise was performed throughout the study in conjunction with testosterone treatment.

Future research is warranted to investigate if testosterone treatment together with resistance exercise training provides greater benefits than either alone. This is an important issue, as numerous studies have shown that a greater muscle strength (assessed by either the hand grip test, leg press, leg extension or chest press) is associated with a significant reduction in mortality, in both the general population as well as in clinical populations.30

Poor handgrip strength has also been linked to premature mortality in the oldest old population according to the findings of the Leiden 85-plus study.31 Risk for all-cause mortality was significantly increased among participants in the lowest tertile of handgrip strength at age 85 years by 35%, and the lowest two tertiles of handgrip strength at age 89 years by 104% and 73%, respectively.31 Interestingly, in this study it was also found that handgrip strength has a greater impact on mortality than old age. Furthermore, participants with a greater decline in strength over four years had a significantly elevated mortality risk by 72%.31 This is especially relevant to the results in the TEAAM trial, as men in the placebo group had a decline in muscle mass, power, and physical function over time, while testosterone treated men showed increases in these parameters.8 This suggests that testosterone treatment plays a role in attenuating the age-related decline in muscle mass, power, and physical function. Support for this comes from the TOM (Testosterone in Older Men with Mobility Limitations) Trial, which showed that testosterone treatment not only resulted in patient-important improvements in muscle strength and stair-climbing power 17, but also significantly attenuated the age-related decline in aerobic capacity.32 Like muscle strength, aerobic capacity (also known as cardiorespiratory fitness, CRF) is associated with a marked reduction in mortality in the general population 33, as well as in people with the metabolic syndrome and depression.34 Notably, regardless of strength, individuals with higher CRF have a longer life expectancy than low CRF peers.35 Over the past three decades, CRF has emerged as a strong, independent predictor of all-cause and disease-specific mortality. The evidence supporting the prognostic use of CRF is so powerful that the American Heart Association recently advocated for the routine assessment of CRF as a clinical vital sign.

Other 3 year-long RCTs have investigated the effects of testosterone treatment on body composition.36 Snyder et al. showed that testosterone treatment – which increased testosterone levels from 367 ng/dL (12.7 nmol/L) before treatment to 625 ng/dL (21.7 nmol/L) by the sixth month of treatment and remained at that level for the remaining 3 years - significantly decreased fat mass (-2.9 kg) and increased lean mass (1.9 kg), whereas no change was seen in the placebo-treated men.36 Page et al. showed that testosterone treatment – which increased testosterone levels from 288 to 479 ng/dL (10.0 to 16.6 nmol/L) - significantly decreased fat mass (-5.5%) and increased lean mass (3.77 kg), whereas no change was seen in the placebo-treated men.6 Testosterone treated men had a significant improvement in handgrip strength and performance in a timed functional test when compared with baseline and placebo. As was also shown in the TEAAM study, placebo treated men in the study by Page had deterioration in performance parameters. This supports the notion that without testosterone treatment, there is a decline in physical function over time in older men with low or low-normal testosterone levels who are not receiving testosterone treatment.

Objective measures of physical capacity – such as those tested in the TEAAM and TOM trials - are predictors of all-cause mortality in older populations, and may therefore provide useful tools for identifying older people at higher risk of death.37 Interestingly, a new terminology “skeletal muscle function deficit” has been proposed to embrace the evolving conceptualization of sarcopenia and other age-related muscle dysfunctions.38 It comprises a variety of contributory etiologies and has the potential to provide a framework for developing diagnostic categories that are useful for both clinical practice and research.38 The diagnostic criteria for skeletal muscle function deficit are the same measures of muscle performance - strength, power, endurance (fatigability) – that were evaluated in the TEAAM trial. Future studies are needed to investigate the role of testosterone in the prevention of both age-related muscle mass loss, performance decline and the development of skeletal muscle function deficit.